Early Detection of Kawasaki Disease in Infants

BACKGROUND AND OBJECTIVES: This study aimed to investigate the clinical characteristics of infantile Kawasaki disease (KD), and to evaluate early diagnostic features of KD in febrile infants. SUBJECTS AND METHODS: We retrospectively reviewed the medical records of 64 KD patients from January 2010 to October 2014. There was an analysis of the clinical, laboratory data of the infants versus children groups. Furthermore, the clinical and laboratory data of infantile KD patients were compared with 16 infants who were admitted for other acute febrile diseases. RESULTS: A total of 64 patients with KD were identified; 20 (31.3%) were infants; 44 (68.8%) were >1 year old children. Incomplete KD was much more common in infants (n=13, 65.0%) than in children group (n=14, 31.8%) (p=0.013). The infants were characterized by significantly higher rates of inflammatory changes at the Bacille Calmett-Guerin (BCG) inoculation site (p<0.001), but lower rates of changes in the extremities (p=0.029) and cervical lymphadenopathy (p=0.006). The serum levels of platelet after 1 week (p=0.005), C-reactive protein (p=0.038), and N-terminal pro-brain natriuretic peptide (NT-proBNP) (p=0.026) were all significantly higher in the infants group. Comparing the infants with KD versus the other acute febrile diseases, there were significantly higher serum levels of erythrocyte sedimentation rate (p=0.002), C-reactive protein (p=0.046) and NT-proBNP (p=0.001) for the infants with KD group. CONCLUSION: BCGitis and higher levels of NT-proBNP can be helpful for early diagnosis of the incomplete KD in infants, and may be a good predictor of KD in acute febrile infants, when combined with other acute phase reactants.

Nidogen Plays a Role in the Regenerative Axon Growth of Adult Sensory Neurons Through Schwann Cells

We previously reported that nidogen is an extracellular matrix protein regulating Schwann cell proliferation and migration. Since Schwann cells play a critical role in peripheral nerve regeneration, nidogen may play a role in it via regulation of Schwann cells. Here, we demonstrate direct evidence that nidogen induces elongation of regenerative axon growth of adult sensory neurons, and that the effect is Schwann cell dependent. Continuous infusion of recombinant ectodomain of tumor endothelial marker 7, which specifically blocks nidogen function in Schwann cells, suppressed regenerative neurite growth in a sciatic nerve axotomy model. Taken together, it is likely that nidogen is required for proper regeneration of peripheral nerves after injury.

Janus Kinase 2 Inhibitor AG490 Inhibits the STAT3 Signaling Pathway by Suppressing Protein Translation of gp130

The binding of interleukin-6 (IL-6) cytokine family ligands to the gp130 receptor complex activates the Janus kinase (JAK)/ signal transducer and activator of transcription 3 (STAT3) signal transduction pathway, where STAT3 plays an important role in cell survival and tumorigenesis. Constitutive activation of STAT3 has been frequently observed in many cancer tissues, and thus, blocking of the gp130 signaling pathway, at the JAK level, might be a useful therapeutic approach for the suppression of STAT3 activity, as anticancer therapy. AG490 is a tyrphostin tyrosine kinase inhibitor that has been extensively used for inhibiting JAK2 in vitro and in vivo. In this study, we demonstrate a novel mechanism associated with AG490 that inhibits the JAK/STAT3 pathway. AG490 induced downregulation of gp130, a common receptor for the IL-6 cytokine family compounds, but not JAK2 or STAT3, within three hours of exposure. The downregulation of gp130 was not caused by enhanced degradation of gp130 or by inhibition of mRNA transcription. It most likely occurred by translation inhibition of gp130 in association with phosphorylation of the eukaryotic initiation factor-2alpha. The inhibition of protein synthesis of gp130 by AG490 led to immediate loss of mature gp130 in cell membranes, due to its short half-life, thereby resulting in reduction in the STAT3 response to IL-6. Taken together, these results suggest that AG490 blocks the STAT3 activation pathway via a novel pathway.

Netrin-1 Specifically Enhances Cell Spreading on Fibronectin in Human Glioblastoma Cells

Netrins are secreted molecules and involved in axon guidance, cell migration and tumor development. Recent studies revealed that netrins perform novel functions in such processes as epithelial development and angiogenesis without operating through the classical netrin receptors, DCC (Deleted in Colorectal Cancer) and Unc5h. In the present study, we investigated the roles of netrin-1 and its receptors in cell spreading of human glioblastoma cells, and found that netrin-1 haptotactically enhanced fibronectin-induced cell spreading and focal adhesion formation in U373 glioblastoma cells. Netrin-1 binding to the U373 cell membrane was blocked by an antibody against alpha v integrin subunit, but not by an anti-DCC or anti-Unc5h antibody. In addition, enhancement of the fibronectin response by netrin-1 was abrogated by a function blocking antibody against integrin alpha v beta 3. Since the alpha v subunit of the integrin family plays an important role in the pathophysiological aspects of cell migration, including tumor angiogenesis and metastasis, our data provide important insight into the molecular mechanism of netrin function.

Tyrphostin ErbB2 Inhibitors AG825 and AG879 Have Non-specific Suppressive Effects on gp130/ STAT3 Signaling

Although the interaction between gp130 and the ErbB family has frequently been shown in cancer cells, the mechanism of this interaction remains unclear and controversial. In the present study, we found that specific tyrphostin inhibitors of ErbB2 (AG825 and AG879), but not ErbB1 inhibitor (AG1478), suppressed IL-6-induced tyrosine phosphorylation of STAT3 in schwannoma cells. However, biochemical evidence for transactivation of ErbB2 by IL-6 was not observed. Additionally, the inhibition of ErbB2 expression, with either a specific RNAi or transfection of an ErbB2 mutant lacking the intracellular domain did not inhibit the IL-6-induced tyrosine phosphorylation of STAT3. Thus, it seems that tyrphostins, which are known as specific inhibitors of the ErbB2 kinase, may have non-specific suppressive effects on the IL-6/STAT3 pathway.

Netrin Inhibits Regenerative Axon Growth of Adult Dorsal Root Ganglion Neurons in Vitro

Netrin is a neuronal guidance molecule implicated in the development of spinal commissural neurons and cortical neurons. The attractive function of netrin requires the receptor, Deleted in Colorectal Cancer (DCC), while the receptor Unc5h is involved in the repulsive action of netrin during embryonic development. Although the expression of netrin and its receptor has been demonstrated in the adult nervous system, the function of netrin in adult neurons has not yet been elucidated. Here, we show that netrin treatment inhibited neurite outgrowth of adult dorsal root ganglion (DRG) neurons in explant and dissociated cultures. In addition, unc5h1-3 mRNAs, but not the dcc mRNA, are abundantly expressed in the adult DRG. An in situ hybridization study demonstrated that unc5h mRNAs were expressed in DRG neurons. This finding indicates that netrin/Unc5h signaling may play a role in the neurite outgrowth of adult DRG neurons and that netrin may be involved in the regulation of peripheral nerve regeneration.

Postnatal Developmental Expression of TEM7 mRNA and its Putative Ligand in the Rat Cerebellum / 대한해부학회지

Tumor endothelial marker 7 (TEM7) is a putative transmembrane protein that is highly expressed in the tumor endothelium and cerebellar neurons. In the present study, the expression profile of TEM7 mRNA and its putative ligand in the developing cerebellum of the rat was investigated using in situ hybridization and ligand binding assay. The secreted recombinant ectodomain of TEM7 was employed to label the expression of putative ligand of TEM7 in the cerebellum. The expression of a putative ligand of TEM7 demonstrated by using TEM7 ectodomain was found in the molecular layer of the cerebellum, where the dendritic trees of Purkinje cells are present. A developmental study has shown that TEM7 mRNA expression in the Purkinje neurons was increased with age during postnatal development, whereas the putative ligand labeling in the molecular layer was observed throughout the developmental period. These findings indicate that TEM7-ligand interaction plays a role in the differentiation of Purkinje cells during postnatal development.

Immunohistochemical Study on the Distribution of Tumor Endothelial Marker 7 in the Rat Forebrain / 대한해부학회지

Tumor endothelial marker 7 (TEM7) is a putative transmembrane protein that is highly expressed in the tumor endothelium. In the present study, the expression profile of TEM7 in the rat forebrain was investigated using immunohistochemistry with a specific polyclonal antibody against the extracellular region of TEM7. The immunohistochemical research revealed that TEM7 expressions were localized to specific neuronal areas such as cerebral cortex, hippocampus and hypothalamic magnocellular nuclei. The TEM7 protein was mainly present in the dendrite and cell body of the projection neurons. However, glial cells, vascular endothelial cells and meningeal cells did not show the expression of TEM7, indicating the specific roles of TEM7 in the neuronal cells in the vertebrate nervous system.